Mitotane is the only drug currently available which is effective in the treatment of metastatic adrenal carcinoma. In the doses generally recommended for this purpose, the drug causes severe side effects which ultimately limit its use. Low doses of Mitotane are better tolerated and have been used effectively as adjuvant therapy in the treatment of adrenal carcinoma as well as in the medical treatment of nonneoplastic forms of Cushing's syndrome. Toxic side effects, however, still occur with low doses. The major metabolite of Mitotane is DDA, an inactive diphenylacetic acid derivative. It had been proposed that the efficacy of Mitotane could be enhanced if the metabolic formation of this metabolite could be reduced. Recently, a methylated analog of Mitotane (Mitometh) has been synthesized. The methyl group blocks the formation of DDA. Preliminary biological studies in the guinea pig have shown that Mitometh has adrenolytic activity essentially equivalent to that of Mitotane but with much less toxicity. The main objective of the proposed study is to investigate Mitometh as an adrenolytic drug and to determine its therapeutic effectiveness on adrenal cancer and other non-neoplastic adrenocortical diseases. We propose to: 1) Prepare sufficient quantities of Mitometh for toxicological studies and, if indicated, for subsequent clinical trial; 2) Formulate the drug for oral administration and carry out quality control procedures; 3) Study its pharmacokinetics and organ concentration in the rat, guinea pig and dog; and 4) Conduct clinical trials in patients with functioning and nonfunctioning adrenal carcinoma who have developed metastases or in whom Mitotane had been used as adjuvant therapy following resection of the primary tumor. If effective and with lower toxicity than Mitotane, Mitometh will be tried as an adrenolytic drug in the therapy of nonneoplastic types of adrenal hyperfunction. These studies with Mitometh should disclose whether this compound will offer improved therapy and prognosis with adrenal carcinoma. If effective, this drug may be important in the medical treatment of nonneoplastic types of adrenal hyperfunction.